Thyroid cancer derived from the follicular epithelial cell is the most common endocrine cancer. Papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) account for the great majority of all thyroid malignancies (1). An estimated 7% of the adult population (275,000 in 1999 in the United States alone) develops clinically significant thyroid nodules during their lifetime (2). The advent of thyroid ultrasound now allows for an increasing number of nodules to be diagnosed, and it is now recognized that nodules are present in an estimated 50% of the general population and are detected at a subclinical level. Because only 10% of these nodules will be a true malignancy, preoperative testing to differentiate benign from malignant nodules has been developed (3,4). Currently, fine needle aspiration (FNA) biopsy is the best diagnostic tool available for preoperative diagnosis. The FNA-based cytological diagnosis can be straightforward. However, approximately 20% (ranging from 9.2-42%) of all FNA will result in an inconclusive or suspicious outcome, especially if a follicular proliferation is found; the differentiation between a benign follicular neoplasia, especially follicular adenomas (FAs), and FTC based on the morphological features on FNA cytology is virtually impossible (5-8).
Therefore, because of the obvious difficulty in such preoperative diagnoses, surgical removal of the involved thyroid gland is routinely performed for diagnostic purposes in the setting of thyroid nodules and follicular cytology. However, in only 10-20% of these cases would a follicular thyroid malignancy be found on final histology, resulting in unnecessary surgery for the vast majority of patients (4-6, 8, 9). More importantly, false-negative cytologies can lead to delayed treatment with potentially serious consequences for the patient (10).
Regarding the obvious limitation of FNA cytology in the preoperative diagnosis, there is a clinical need for new, reliable preoperative markers to distinguish benign from malignant thyroid nodules. Nonetheless, whereas numerous assays have been developed in an attempt to reduce these inconclusive preoperative diagnoses, none has yet proven more successful than FNA cytology in the clinical setting (4, 11-13). A possible underlying cause for this clinical problem is the continued limited understanding of the biological relationship of the different benign thyroid neoplasias to each other and to thyroid carcinoma, despite much research in this field (11, 14-17).
Therefore, to directly address the clinically relevant issue, we sought to elucidate further the molecular differences between benign follicular neoplasia and FTC. We took a global expression array approach to dissect out the minimal number of genes that can play a fundamental role in the early steps of FTC carcinogenesis, thus, not only giving new biological insight, but also allowing us to differentiate FTC, even at the minimally invasive stage, from benign follicular neoplasia by evaluating expression of a limited set of genes. The use of objective molecular markers will serve as an adjunct in the preoperative diagnosis of follicular thyroid cancer.